Zwitterionic Manganese and Gadolinium Metal–Organic Frameworks

Nov 16, 2017 - Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, W...
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Research Article Cite This: ACS Appl. Mater. Interfaces XXXX, XXX, XXX-XXX

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Zwitterionic Manganese and Gadolinium Metal−Organic Frameworks as Efficient Contrast Agents for in Vivo Magnetic Resonance Imaging Liang Qin,†,§,# Zi-Yan Sun,‡,∥,# Kai Cheng,∥ Shu-Wen Liu,† Jian-Xin Pang,† Li-Ming Xia,‡ Wen-Hua Chen,*,† Zhen Cheng,*,∥ and Jin-Xiang Chen*,† †

Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China ‡ Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China § School of Chemistry and Chemical Engineering, Zhaoqing University, Zhaoqing 526061, China ∥ Department of Radiology, School of Medicine, Stanford University, 1201 Welch Road, Lucas Center, Stanford, California 94305-5484, United States S Supporting Information *

ABSTRACT: Two water-stable three-dimensional Mn- and Gd-based metal−organic frameworks (MOFs), {[Mn2(Cmdcp)2(H2O)2]·H2O}n (1) and {[Gd(Cmdcp)(H2O)3](NO3)·3H2O}n (2, H3CmdcpBr = N-(4-carboxy benzyl)-(3,5-dicarboxyl)pyridinium bromide), have been prepared and analyzed. In vitro magnetic resonance imaging indicated that MOFs 1 and 2 possess relaxivity r1 values of 17.50 and 13.46 mM−1·S−1, respectively, which are superior to that of the control Gd-DTPA (r1 = 4.87 mM−1·S−1, DTPA = diethylene triamine pentaacetate). MOFs 1 and 2 also possessed good biocompatibility and low cytotoxicity against a model cell line. In vivo magnetic resonance images of treated Kunming mice indicated that kidneys showed remarkably positive signal enhancement after 15 min with intravenous administration of MOF 1 and the hyperintensity of both kidneys persisted for about 240 min with no obvious tissue damage. MOF 1 is therefore promising in vivo probes for imaging intravascular diseases and renal dysfunction. KEYWORDS: zwitterionic carboxylate, manganese and gadolinium, metal−organic framework, water-stable, MRI agent

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INTRODUCTION Magnetic resonance imaging (MRI) is a mighty, nonpuncture clinical diagnostic technique.1−6 It differentiates abnormalities from normal tissues based on NMR water proton signal variation as a result of altered water densities and/or nuclear relaxation rates.7−9 Compounds of highly paramagnetic metal ions, such as Gd3+ and Mn2+, are widely adopted as MRI reagents.10−13 Gd3+ has an electron spin of S = 7/2 with low electronic relaxation. Thus, Gd-based compounds, such as Magnevist (Gd-DTPA, DTPA = diethylene triamine pentaacetate) and Dotarem ([Gd(DOTA)(H2O)], DOTA = 1,4,7,10tetraazacyclododecane-1,4,7,10-tetraacetic acid), are clinically the privileged MRI positive contrast agents. A disadvantage of gadolinium-based contrast agents, however, is their only moderate longitudinal (r1) relaxation rates and therefore the requirement for the administration of the approved dose two to three times to achieve high image quality (several grams per patient).14,15 The latter is a serious concern for patients with severe kidney failure. Metal−organic frameworks (MOFs) have recently arisen as potential MRI agents and are receiving increased attention © XXXX American Chemical Society

because of the possibility of three-dimensional (3D) images with high spatial resolution.16−25 MOFs are an emerging type of hybrid materials constructed from metal ions or metal clusters as nodes and organic ligands as struts. They have shown potential in diverse fields, such as gas treatment (adsorption, storage, and separation),26−28 nonlinear optics,29,30 catalysis,31−33 and biomedical applications.34−37 MOFs could potentially offer advantages as MRI agents owing to its ability to carry large numbers of paramagnetic metal ions. MOFs of Gd3+ and Mn2+ are promising T1-weighted contrast agents exhibiting large per metal- and particle-based MRI relaxivities.38,39 Recently, Mn2+ centers in MOFs were reported to exhibit high in vivo r1 MR relaxivity through binding to intracellular proteins. Water stability and solubility are prerequisites for MOFs to function in an in vivo environment. However, water instability and insolubility are unfortunately intrinsic to many MOFs.40 Received: July 3, 2017 Accepted: November 7, 2017

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DOI: 10.1021/acsami.7b09608 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

Research Article

ACS Applied Materials & Interfaces

1232 (w), 1174 (w), 1135 (w), 1027 (w), 912 (w), 782 (m), 768 (m), 739 (m), 727 (m), 718 (m), 628 (m), 577 (w). {[Gd(Cmdcp)(H 2 O) 3 ](NO 3 )·3H 2 O} n (2). To a solution of H3CmdcpBr (28 mg, 0.09 mmol) in H2O (5 mL) was added 0.1 M NaOH to adjust the pH to 6.0. Gd(NO3)3·6H2O (27 mg, 0.06 mmol) in H2O (1 mL) was added, and the clear colorless solution was stirred for 0.5 h and allowed to stand at rt for 1 week. The colorless crystals formed were collected by filtration and dried in vacuum to afford MOF 2 (31 mg, 56%). Anal. Calcd for C9H17GdN2O15·2H2O: C, 21.01; H, 2.55; N, 5.45. Found: C, 20.69; H, 2.01; N, 5.81. IR (KBr disc, cm−1) ν: 3410 (s), 1647 (s), 1610 (s), 1390 (s), 1238 (m), 1175 (w), 1114 (w), 935 (m), 770 (m), 728 (m), 630 (m), 520 (m). X-ray Crystal Structure Determinations. Single-crystal X-ray crystallographic studies for 1 and 2 were carried out on a Bruker APEX II diffractometer coupled with graphite-monochromated Mo Kα (λ = 0.71073 Å) irradiation. The data were corrected for absorption effects with SADABS.44 Both structures were solved via direct methods and refined on F2 using full-matrix least-squares techniques with the SHELXTL-97 program.45 For MOF 1, the hydrogen coordinates for the water molecules were estimated by Calc-OH program in WinGX suite, and the water molecules were subsequently treated as rigid groups with O−H = 0.85 Å and thermal parameters constrained to Uiso(H) = 1.2Ueq(O). For MOF 2, the hydrogen coordinates of the water molecules were identified from Fourier maps and applied O−H = 0.82 Å and Uiso(H) = 1.2Ueq(O) for the bond distance and the thermal parameters. CCDC numbers for 1 and 2 are 1057253 and 1057254, respectively. The key crystallographic data for 1 and 2 are summarized in Table 1, whereas pertinent bond parameters for MOFs 1 and 2 are summarized in Tables S1 and S2.

We herein report the synthesis of two water-stable manganese and gadolinium MOFs of N-(4-carboxybenzyl)(3,5-dicarboxyl)pyridinium bromide (H3CmdcpBr, Chart 1),41−43 namely, {[Mn2(Cmdcp)2(H2O)2]·H2O}n (1) and Chart 1. Structure of H3CmdcpBr

{[Gd(Cmdcp)(H2O)3] (NO3)·3H2O}n (2), together with their structures and physical characterization data. Both 1 and 2 demonstrate increased T1 relaxivities and excellent stability under physiological conditions. The in vitro biocompatibilities of 1 and 2 have also been assessed, and MOF1 shows remarkable kidney-positive signal enhancement.

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EXPERIMENTAL SECTION

Materials and Methods. H3CmdcpBr was synthesized according to our previous method.41 All other reagents were directly available from suppliers and used as received. IR spectra were collected with a Nicolet Magna-IR 550 infrared spectrometer. Combustion data were collected with an EA1110 CHNS elemental analyzer. Thermogravimetric analysis (TGA) was carried out on an SDTA851 thermogravimetric analyzer. Powder X-ray diffraction (PXRD) spectra were collected with a Rigaku D/Max-2200/PC. The average hydrodynamic particle sizes of 1 and 2 were analyzed with dynamic light scattering (DLS) on a Zetasizer Nano ZS90 (Malvern, UK) at 25 °C. Transmission electron microscopy (TEM) images were collected on a Hitachi H-800 transmission electron microscope with an accelerating voltage of 200 kV. MRI measurements were performed on a 0.5 T MRI system (SPEC-RC2, Beijing SPEC Corp.) and a 3.0 T benchtop MRI system (MRS 3000, MR Solutions, Guildford, UK). Human embryonic kidney cell line (HEK293) was commercially available from the cell bank of the Chinese Academy of Sciences (Shanghai, China) and was routinely cultured in ATCC-formulated Dulbecco’s modified Eagle’s medium (DMEM) (Invitrogen) with 10% fetal bovine serum (10% FBS) as well as 1% antibiotics (1% PS, penicillin−streptomycin, 10 000 U·mL−1). The cell line was maintained in 150 mm diameter Primaria dishes at 37 °C with saturated humidity under 5% CO2. The medium was refreshed every 24−48 h. Healthy, young, nonpregnant, and nulliparous Kunming mice (24−27 g) were commercially available from the Laboratory Animal Center of Southern Medical University, China. Animal experiment protocols were approved by the Administrative Panel on Laboratory Animal Care (APLAC) at Stanford University and carried out following the recommendations of the American Association for the Accreditation of Laboratory Animal Care. Female nude mice (6−8 weeks, 18 ± 2 g, Charles River Laboratories) were used for in vivo studies. Synthesis of 1 and 2. {[Mn2(Cmdcp)2(H2O)2]·H 2O}n (1). H3CmdcpBr (92 mg, 0.3 mmol) was suspended in water (25 mL), and 0.1 M NaOH was added to adjust the pH to 7.0. A solution of MnCl2 (38 mg, 0.3 mmol) in H2O (20 mL) was then introduced. The mixture formed was further stirred at 100 °C for 0.5 h, cooled to ambient temperature, and filtered. The resulting light yellow solution was maintained at room temperature (rt) for several days and yielded yellow crystals of MOF 1 (78 mg, 85%). Anal. Calcd for C18H16Mn2N2O15: C, 35.43; H, 2.64; N, 4.59. Found: C, 35.13; H, 2.74; N, 4.48. IR (KBr disc, cm−1) ν: 3394 (s), 3203 (s), 3014 (s), 2947 (s), 1669 (s), 1622 (s), 1601 (s), 1446 (m), 1384 (s), 1356 (s),

Table 1. Crystallographic Data for MOFs 1 and 2 compound

1

2

molecular formula formula weight crystal system space group a (Å) b (Å) c (Å) β (deg) V (Å3) Z T/K Dcalc (g cm−3) λ(Mo Kα) (Å) μ (cm−1) total reflections unique reflections no. observations no. parameters Ra wRb GOFc Δρmax (e Å−3) >Δρmin (e Å−3)

C18H16Mn2N2O15 610.21 monoclinic P21/c 7.5910(5) 17.6666(12) 15.5193(11) 98.904(2) 2056.2(2) 4 296(2) 1.971 0.71075 1.32 20 974 4700 3723 337 0.0527 0.1004 1.112 0.835 −0.565

C9H17GdN2O15 550.5 monoclinic P21/n 10.1468(6) 15.5239(9) 10.5159(6) 102.2020(10) 1619.02(16) 4 296(2) 2.258 0.71073 4.185 10 257 2918 2687 280 0.0236 0.0651 1.108 1.812 −1.374

R = Σ||Fo| − |Fc|/Σ|Fo||. bwR = {Σw(Fo2 − Fc2)2/Σw(Fo2)2}1/2. cGOF = {Σ[w((Fo2 − Fc2)2)]/(n − p)}1/2, where n denotes the number of reflections and p denotes the total numbers of parameters refined. a

Longitudinal Relaxation Time Measurements. The measurement of longitudinal relaxation times T1 was conducted at 30 °C. Five samples of MOF 1 or 2 were prepared with concentrations of 31.25, 62.5, 125, 250, and 500 μM in deionized water. These samples were ultrasonicated for 2 min to ensure solubilization. The T1 values of the MOF solutions were corrected for the T1 of pure deionized water or of 100 μM Tris-HCl buffer (pH 6.4, 100 mM NaCl, 5 mM MgCl2). The B

DOI: 10.1021/acsami.7b09608 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Figure 1. PXRD of MOFs 1 (a) and 2 (b) showing agreement among the simulated, synthesized, and powder after immersion in serum, H2O, PBS, and DMEM for 10 days. 256 × 256 matrices, NEX of 3, a FOV of 4 cm, and a slice thickness of 0.5 mm. In Vivo Toxicity Analysis. In vivo toxicity was estimated in healthy, young, nonpregnant, and nulliparous Kunming mice (24−27 g). The animals were placed in clean polypropylene cages with feeding access and maintained in an animal house at 20 ± 2 °C coupled with 50−70% relative humidity and with a 12 h light/dark cycle. The animals were provided with a commercial mice pellet diet. After 1 week of acclimation, the mice were randomly divided into six groups, including one control group and five experimental groups with MOFs 1, 2, or Gd-DTPA, phosphate-buffered saline (PBS) (1×, pH = 7.4), and Tris-HCl (pH 7.4, 100 mM NaCl, 5 mM MgCl2) buffer solution. Each group consisted of five females and five males and was kept separately in polypropylene cages. Each solution (100 μL) with a concentration of 500 μM MOFs 1, 2, or Gd-DTPA was intravenously injected into a tail vein. The above experiment was carried out three times, after 4 h for the first set of experiment, 10 days for the second, and 20 days for the third. The animals were sacrificed, and their heart, liver, spleen, lungs, kidneys, and intestine were removed, stained with hematoxylin−eosin, and examined under light microscopy. Biodistribution Mn(II) and Gd(II) elemental analyses were carried out with inductively coupled plasma mass spectrometry (ICP−MS, Thermo Scientific X series 2 Quadrupole). Tissues were harvested from mice (three mice each group) for biodistribution at 1 and 24 h after intravenous injection to quantitatively assess the biodistribution of MOFs 1 and 2 within various organs. The organs (not more than 500 mg) were digested in a microwave (CEM MarsXpress microwave digester with Teflon microwave-safe vessels) before ICP analysis. The samples were dissolved in freshly prepared aqua regia [trace metal grade, 70% HNO3/36% HCl (Fisher Scientific), 1:3 v/v] and diluted to 8 mL with double-distilled water. The distribution of normal tissue and organs was expressed as a percentage of the injected dose per gram of tissue (% ID·g−1).

measurement time for each sample was ca. 2 min, 24 h in pure deionized water, and 24 h in Tris-HCl buffer. The relaxivity value, r1 (mM−1·S−1), was calculated from the slope of the plot of 1/T1 versus the concentration of MOF 1 or 2. T1 mapping images were acquired by an inversion recovery sequence [echo time (TE)/repetition time (TR) = 11/4000 ms] with inversion times (TI) of 200, 300, 400, 500, 600, and 700 ms. Signal intensities were measured on each image by drawing the regions of interest in the center of each vial. The T1 relaxation times were calculated by fitting the acquired inversion recovery images into the following equation: M = M0 (1 − 2 exp(−TI/ T1) + exp(−TR/T1)), where M and M0 are the measured and initial magnetizations, respectively. All data fittings were carried out using a nonlinear least-squares algorithm by OriginPro 8.1 SR2 (OriginLab Co.) analysis software. MTT Assay. The cytotoxicities of MOFs 1 and 2 were evaluated against normal human embryonic kidney cell line HEK293 using the MTT assay. These cells were cultured in DMEM with 10% FBS in the presence of 100 μg·mL−1 streptomycin and 100 U·mL−1 penicillin at 37 °C under a 5% CO2 atmosphere. After centrifugation at 1500 g for 5 min, cell pellets were resuspended in the respective medium at a concentration of 3 × 104 cells·mL−1 and seeded in 96-well plates at 100 μL with 3 × 104 cells/well. MOFs 1 and 2 and Gd-DTPA (positive control) were diluted with distilled water and applied in the final concentrations from 15.6 to 500 μM (four wells for each concentration per plate). The plates were incubated for 72 h, and MTT was subsequently added to a final concentration of 0.5 mg·mL−1 per well. This is followed by an additional incubation time of 4 h. The reaction was then stopped, and the formazan dye was solubilized by adding 150 μL of DMSO. Optical density was measured at 490 nm using a Bio-Rad 3500 microplate reader (Bio-Rad, Hercules, CA, USA). Each experiment was carried out three times, and the mean was determined. Data are reported as mean ± SD, and all statistical analyses were performed by SPSS 11.0. A significant difference between the experimental and control groups was evaluated using the T-test method (P < 0.05). The cell viability was calculated by

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RESULTS AND DISCUSSION Choice of Materials. We choose a polar zwitterionic ligand for MOF construction to endow solubility and stability in aqueous environments. The MOFs synthesized accordingly had additional advantages, including increased metal loading, facile particle formation (compared to molecular Gd-DTPA),38,39 and lower inherent toxicity. The network structures of MOFs also serve to encapsulate potentially toxic metal ions in the inner particle to help mitigate toxicity. This toxicity is further reduced by the much slower degradation of the MOF structures compared to their single molecular counterparts.16 Synthesis and Characterization of MOFs 1 and 2. MOFs 1 and 2 were obtained from the reaction of H3CmdcpBr with MnCl2 and Gd(NO3)3, respectively, in the presence of NaOH. The pyridinium carboxylate zwitterionic ligand has a stable, polar backbone and is soluble in polar media, such as

Cell viability (%) = [(OD1 − OD3)/(OD2 − OD3)] × 100% where OD1, OD2, and OD3 are the optical densities of cell culture with and without the sample and of the medium, respectively. In Vivo MRI. Testing was performed using female nude mice (6−8 weeks, 18 ± 2 g, n = 3, Charles River Laboratories) and involved the injection of MOF 1 (300 μL, 2.7 mg Mn·kg−1 mouse body weight) into the tail vein and measurement with a 3.0 T small animal MRI scanner with a magnetic bore size of 310 mm, a maximum gradient amplitude of 600 mT/m, and a maximum slew rate of 2500 T/m/s. T1-weighted MR images of liver and kidneys were acquired using a fast-spin echo sequence with the following parameters: TE/TR: 10/ 750 ms, 256 × 256 matrix, number of excitations (NEX): 1, field of view (FOV): 4 cm, and slice thickness: 1.0 mm. Three-dimensional contrast-enhanced MR angiography of the aorta, renal artery, and inferior vena cava (IVC) was performed using the 3D fast spoiled gradient echo with the following parameters: TE/TR of 1.7/5.3 ms, C

DOI: 10.1021/acsami.7b09608 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Figure 2. (a) Coordination environment of Mn(1) and Mn(3). (b) Three-dimensional structure of 1 viewed along the a axis (dissociated water molecules are omitted). (c) Coordination environment of Mn(2). Color codes: Mn(1): teal, Mn(2): orange, Mn(3): purple, O: red, N: blue, and C: black.

Figure 3. (a) Gd2 cluster structure in 2. (b) Monocapped square-antiprismatic coordination sphere of Gd(III). (c) Three-dimensional structure of 2 viewed along the c axis (NO3− and dissociated water molecules are omitted). Color codes: Gd: purple, O: red, N: blue, and C: black.

MeOH and H2O.46 Upon ultrasonication, MOFs 1 and 2 solubilized in water to maximum concentrations of approximately 2 mM for 1 and 500 μM for 2. The PXRD patterns of 1 and 2 after immersion in rat serum, H2O, DMEM (10% FBS, 1% PS), or PBS (1×, pH = 7.4) for 10 days matched the theoretical patterns, indicating their bulky phase purity and material stability (Figure 1). The bulk purity of MOFs 1 and 2 was also confirmed by combustion analyses. TGAs indicated that both 1 and 2 are stable up to 250 and 300 °C, respectively. For 1, the weight loss of 8.96% from 30 to 272 °C corresponds to the loss of one lattice water molecule and two coordinated water molecules (calculated 8.85%). For 2, the weight loss of 13.17% from 30 to 150 °C corresponds to the loss of one lattice water molecule and three coordinated water molecules (calculated 13.21%). The other two lattice water molecules are presumably lost during the air-drying process (Figure S1). TEM micrographs of 1 and 2 gave diameter sizes of 50.0 ± 6.7 nm for 1 and 70.0 ± 8.2 nm for 2 (Figure S2). DLS measurements were also carried out to estimate the hydrodynamic radii of the as-synthesized 1 and 2 in H2O. As shown in Figure S3, the hydrodynamic radii were 81.15 ± 13.82 nm for 1 and 90.34 ± 12.21 nm for 2. DLS measurements are anticipated to give an average hydrodynamic radius rather than the actual size of the nanoparticles, so the particle sizes obtained from DLS are higher than those from the TEM study.47 The average radius of MOF 2 remains constant in urine for 2 weeks, which further indicates its good stability (Figure S3). Crystal Structures of MOFs 1 and 2. {[Mn2(Cmdcp)2(H2O)2]·H2O}n (1). MOF 1 crystallizes in the monoclinic P21/c space group, and each asymmetric unit consists of three Mn ions being connected by two Cmdcp ligands, with one coordinated and one uncoordinated water molecule. Mn1 has a full occupancy while Mn2 and Mn3 have half occupancies. The complicated 3D structure of 1 can be better understood as the integration of two parts, an hourglassshaped Mn3 cluster supported by Mn1 and Mn3 and a separate

Mn2 ion (Figure S4). The central metal ion of the Mn3 cluster extends to two equivalent Mn1 ions via six μ-COO bridges (Figure 2a). The two apical Mn1 ions are further coordinated by one monodentate COO, one bridging μ-COO to Mn2, and one coordinated water molecule (Figure 2a). Each Mn3 cluster is thus coordinated by 10 Cmdcp ligands and extends to 14 equivalent Mn3 clusters, generating a complicated 3D structure (Figure 2b) with the ligands arranged in such a way that a small void is generated to accommodate one additional Mn2 ion. Thus, Mn2 ion is coordinated by a pair of μ-COO, a pair of the monodentate COO groups, and a pair of coordinated water molecules (Figure 2c). {[Gd(Cmdcp)(H2O)3](NO3)·3H2O}n (2). MOF 2 crystallizes in the monoclinic P21/n space group, and each asymmetric unit consists of one [Gd(Cmdcp)(H2O)3]+ cation, one NO3− anion, and three dissociated water molecules. The 3D structure of 2 can be understood as a pair of Gd3+ ions bridged by four μCOO to yield an overall paddle-wheel-structured Gd2 cluster (Figure 3a). Each Gd center is also associated with one chelating COO and three coordinated water molecules to give a monocapped square-antiprismatic coordination geometry (Figure 3b). Each Gd2 cluster in turn associates with eight equivalent clusters to give an overall 3D network (Figure 3c). In Vitro MRI. Free Mn(II) and Gd(III) ions are harmful to patients because of their tight and irreversible binding to the serum proteins in bones48 and nephrogenic system fibrosis associated with Gd(III)-based contrast agents.49−51 The greater structural integrity of Gd(III)-based MOFs should result in a decreased concentration of free Gd3+ ions in vivo and therefore a reduced risk of these side effects.52,53 Additionally, MOFs have a higher metal loading than their small-molecule counterparts, and their positive T1-weighted signal enhancement ability bodes well for their potential application as MRI contrast agents.54 We, therefore, measured the T1-weighted images and relaxivities of MOFs 1 and 2 and Gd-DTPA as a positive control, in the concentrations ranging from 31.25 to 500 μM with ca. 2 min, 24 h in pure deionized water, and 24 h D

DOI: 10.1021/acsami.7b09608 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Figure 4. (a) T1-weighted MRI images of MOFs 1 and 2 and Gd-DTPA of varying concentrations in water. (b) 1/T1 plots of the concentrations of MOFs 1 and 2 and Gd-DTPA.

Figure 5. (a) Viability of HEK293 cells incubated for 48 h with Gd-DTPA, MOFs 1, and 2 at varying concentrations. Concentrations of free Mn2+ (b) and Gd3+ (c) obtained at different times at 500 μM of MOFs 1 and 2.

viability was estimated to be 95 ± 5% for 1 and 80 ± 3% for 2. Therefore, MOFs 1 and 2 showed good biocompatibility and little cytotoxicity against the model cell line at drug concentrations lower than 500 μM. MOFs 1 and 2 were dissolved in water at a concentration of 500 μM for 48 h, and subsequent ICP−MS analysis (Figure 5b,c) indicated that the leakage rate was increased with the extension of time. As will be discussed later, in in vivo MRI, the signal enhancement was attenuated after 24 h. The ICP−MS result after 24 h shows that MOF 1 had a very limited accumulation in various organs. At 24 h, the leakage rates are 1.3% for Mn2+ (6.5 μM) and 1.2% for Gd3+ (5.8 μM). These low leakage rates are consistent with the low cytotoxicity of these materials. In Vivo MRI. MOF 1 was chosen for further in vivo study because, in addition to its excellent water solubility, it possessed higher r1 relaxivity and lower cytotoxicity than MOF 2. To validate the ability of MOF 1 as a T1-weighted MRI agent in living subjects, we performed in vivo MRI of nude mice (n = 4) injected via the tail vein with MOF 1 (300 μL, 2.7 mg Mn·kg−1 mice body weight, based on ultraviolet−visible (UV−vis) data, Figure S7). The coronal dynamic enhancement images of both kidneys and liver at different time points are shown in Figures 6, S8, and S9. After intravenous administration of MOF 1, both kidneys showed remarkably positive signal enhancement after 15 min compared with the preinjection images. The signal hyperintensity of both kidneys persisted for about 240 min and then slightly attenuated after 24 h (Figures 6a−c and S8), whereas the signal intensity of the liver did not obviously increase even after 60 min (Figure S9). Such a significant difference may be attributed to the accumulation and secretion of the injected 1 in both kidneys. MOF 1 remained within the vascular system for a prolonged time period relative to the conventional small-molecule contrast agent Gd-DTPA (Figure S10, 5 min) under the same conditions. Thus, MOF 1 has potential as an MRI contrast agent for clinical use, especially in

in Tris-HCl buffer (pH 6.4). It is clear that the MRI signal intensity increased with increasing concentration (Figure 4a). The linear plots of 1/T1 versus concentration gave relaxivity r1 values of 17.50 mM−1·S−1 for MOF 1, 13.46 mM−1·S−1 for MOF 2, and 4.87 mM−1·S−1 for Gd-DTPA (Figure 4b) with 2 min in pure deionized water, which are comparable to the values with 24 h in pure deionized water (16.88 mM−1·S−1 for MOF 1, 13.20 mM−1·S−1 for MOF 2, and 4.60 mM−1·S−1 for Gd-DTPA; Figure S5a) and 24 h in Tris-HCl buffer (pH 6.4, 16.19 mM−1·S−1 for MOF 1, 13.00 mM−1·S−1 for MOF 2, and 4.25 mM−1·S−1 for Gd-DTPA; Figure S5b), showing the stability of MOFs 1 and 2 in pure deionized water or Tris-HCl buffer. The relaxivities at 3.0 T (Figure S6) were only slightly higher than those at 0.5 T, indicating that high field strength does not significantly affect the contrast enhancement. Evidently, MOFs 1 and 2 exhibit much higher signal enhancement ability than Gd-DTPA. It should also be noted that both 1 and 2 exhibit much higher r1 relaxivities than clinically used small-molecule contrast agent OmniScan (4.1 mM−1·S−1)55 and nanoscale gadolinium MOF [Gd2(bhc)(H2O)6] (bhc = benzenehexacarboxylate, 1.5 mM−1·S−1).56 The r1 values of 1 or 2 are comparable to those of FDAapproved ultrasmall superparamagnetic iron oxide (Ferumoxytol, 15 mM−1·S−1),57 MOF Gd(BDC)1.5(H2O)2 (BDC = 1,4benzenedicarboxylate, 20.1 mM−1·S−1) with ca. 1 μm in length and 100 nm in diameter, and some other MOFs (Table S3).54 Critically, good water solubility ensures the accessibility of the Mn(II) or Gd(III) centers to bulk water and may contribute to the r1 relaxivities and T1-weighted images.58 These results suggest that 1 and 2 are exploitable as MRI contrast agents. Cytotoxicity. The viability of HEK293 cells incubated with MOFs 1 and 2 of varying concentrations was evaluated using the MTT assay (Figure 5a). No significant decrease in the viability of the HEK293 cells was observed at concentrations below 500 μM. At the concentration of 500 μM, the cell E

DOI: 10.1021/acsami.7b09608 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Figure 6. (a) MR signal intensity from a dynamic study of normal kidneys after intravenous administration of MOF 1. (b) Representative T1weighted images with fast-spin echo sequence from a dynamic MOF 1 contrast-enhanced MR study of both normal kidneys. (c) MR signal intensity from a dynamic study of normal kidneys and liver after intravenous administration of MOF 1. (d) Three-dimensional SPGR shows bilateral renal artery after 20 min intravenous administration of MOF 1. RRA = right renal artery and LRA = left renal artery. (e) Three-dimensional SPGR shows IVC after 40 min intravenous administration of MOF 1.

Figure 7. (a) ICP−MS quantification analysis of MOF 1 in major organs and tissues (Br, brain; Lu, lungs; H, heart; Li, liver; Sp, spleen; SI, small intestine; Ki, kidneys; LN, lymph node; U, urine; and Bd, blood) at 1 and 24 h postinjection. (b) Changes in body weight among the groups with MOFs 1 and 2, Gd-DTPA, PBS, and Tris-HCl and the control groups. (c) Histological morphology images of different organs of Kunming mice exposed to MOF 1, MOF 2, Gd-DTPA (500 μM), PBS, and Tris-HCl for 10 days. Scale bars show 50 μm.

displaying the anatomy and pathology of kidneys. The renal clearance of nanoparticles with sizes of several nanometers is well-known.59 However, our observations suggested that 1 (50.0 ± 6.7 nm) and 2 (70.0 ± 8.2 nm) are too large for the kidneys to absorb. A plausible mechanism might be that these

particles disintegrate into reasonable sizes through collision and gradual decomposition over time.60 Moreover, the 3D spoiled gradient-recalled acquisition (3D-SPGR) echo pulse sequence experiments provided bilateral renal artery images with superior sensitivity and diagnostic accuracy (Figure 6d,e). F

DOI: 10.1021/acsami.7b09608 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Biodistribution. The biodistribution profiles of MOFs 1 and 2 were obtained by ICP−MS quantitative analysis (Figures 7a and S11). More MOF 1 accumulated in the liver and kidneys (18.9 ± 1.3% ID·g−1 and 13.0 ± 1.4% ID·g−1, respectively) than in the intestine and heart (8.9 ± 1.2% ID·g−1 and 7.4 ± 0.1% ID·g−1, respectively) or lungs and spleen (1.4 ± 0.1% ID·g−1 and 1.7 ± 0.5% ID·g−1, respectively). The lowest levels were observed in the brain, blood, and urine (0.3 ± 0.01% ID·g−1, 0.3 ± 0.01% ID·g−1, and 0.1 ± 0.03% ID·g−1, respectively) at 1 h after injection. At 24 h upon injection, the liver (1.29 ± 0.05% ID·g−1), kidneys (2.97 ± 0.16% ID·g−1), spleen, and intestine had very low levels of Mn(II). Although MOF 2 displayed biodistribution levels similar to those of MOF 1 (Figure S11), it did not show any obvious positive MRI signal enhancement in vivo which may be due to its poorer water solubility. The mice of each dose group retained shiny fur without symptoms of poisoning. None died within 10 days after the administration of MOF 1, MOF 2, Gd-DTPA, PBS, or TrisHCl. No obvious change in body weight was observed in the control or experimental animals (Figure 7b). The organ structures from the exposed mice after 4 h, 10, and 20 days were normal and similar to those of the control group (Figures 7c and S12). Cardiac muscle tissue showed no hydropic degeneration. Hepatocytes appeared normal, and there were no inflammatory infiltrates. The glomerulus structure of the kidneys could be easily distinguished. No necrosis was found in any tissue.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (W.-H.C.). *E-mail: [email protected] (Z.C.). *E-mail: [email protected] (J.-X.C.). ORCID

Zi-Yan Sun: 0000-0002-0713-957X Shu-Wen Liu: 0000-0001-6346-5006 Wen-Hua Chen: 0000-0001-5008-5485 Zhen Cheng: 0000-0001-8177-9463 Jin-Xiang Chen: 0000-0002-3963-0718 Author Contributions #

L.Q. and Z.-Y.S. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the financial support from the National Natural Science Foundation of China (nos. 21102070, 81471637), the Natural Science Foundation of Guangdong (2015A030313284), Guangdong Provincial Natural Science Foundation of China (no. 2015A030313284), the Guangdong Provincial Department of Science and Technology of China (no. 2015A010105016), and the Office of Science (BER), the Program for Pearl River New Stars of Science and Technology in Guangzhou (no. 2011J2200071), and U.S. Department of Energy (DE-SC0008397). We are also grateful to Professor David J. Young from University of the Sunshine Coast, Australia, for his insightful comments on this paper. W.-H.C. is grateful to Southern Medical University for financial support.

CONCLUSIONS

We have prepared and structurally authenticated two waterstable Mn(II)- and Gd(III)-based MOFs from a zwitterionic carboxylate ligand. Both MOFs showed good r1 relaxivities and T1-weighted images and very low cytotoxicity toward a human embryonic kidney cell line. These MOFs enabled highresolution MRI through a high contrast efficacy over a prolonged timeframe. The Mn-based MOF 1 has potential as a clinically useful MRI contrast agent, particularly for displaying the anatomy and pathology of vasculature and kidneys.

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Research Article

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.7b09608. Selected bond distances and angles, TGA, TEM images, particle hydrodynamic diameters, r1 relaxivity curves, MRI phantom measurement, and UV−vis absorption spectra of MOFs 1 and 2; Comparison of MRI data for 1 and 2 with the data from reported MOFs; hourglassshaped Mn3 cluster unit in association with an independent Mn ion in 1; MR signal intensity from a dynamic study of normal kidneys after intravenous administration of MOF 1; selected representative images from a dynamic contrast-enhanced MR study of normal kidneys and liver after intravenous administration of MOF 1; ICP−MS quantification analysis of MOF 2 in major organs and tissues; and histological morphology images of different organs of Kunming mice exposed to MOF 1, MOF 2, Gd-DTPA (500 μM), PBS, and TrisHCl for 4 and 20 days (PDF) Crystallographic data of 1 and 2 (CIF) G

DOI: 10.1021/acsami.7b09608 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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DOI: 10.1021/acsami.7b09608 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX